mechanisms of oncogenesis Flashcards
what are some lifestyle factors that are linked to cancer
smoking
obesity and weight
hormones
alcohol
sun and UV
lack of physical activity
poor diet
inherited genes
air pollution
Why is cancer defined as a disease of aging?
The older you get, the higher the risk of developing cancer
The longer we live the more time there is for DNA to accumulate mutations that may lead to cancer
What is cancer?
Disease of the loss of control of cell signalling pathway
Cancer is a group of diseases characterised by 4 distinct hallmarks. What are they?
- Abnormal cell proliferation
- Tumour formation
- Invasion of neighbouring normal tissue
- Metastasis to form new tumours at distant sites
What are carcinomas?
Cancers that occur in the epithelial cells
What are sarcomas?
Cancers that occur in the mesoderm cells (muscle and bone)
What are adenocarcinomas?
Cancers that occur in the glandular tissue
what are the 10 hallmarks of cancer
- evading growth suppressors
- avoiding immune destruction
- enabling replicative immortality
- tumour promoting inflammation
- activating invasion and metastasis
- inducing angiogenesis
- genome instability and mutation
- resisting cell death
- deregulating cellular energetics
- sustained proliferative signaling
what is meant by hallmarks of cancer
all the characteristics a normal cell has to undergo to become a tumour cell
what effect do carcinogens have on DNA
Carcinogens cause alterations to the DNA - mutation
DNA from tumours has been shown to contain many alterations from point mutations to deletions.
how does accumulation of DNA mutations occur and what does it result in
This accumulation occurs only after the cells defense mechanism of DNA repair have been evaded
what is germline mutation
Alteration in DNA (point mutations/deletion) within an egg or sperm cell is known as a germline mutation
can germline mutations be passed onto offspring
These mutations can be passed onto your offspring (it is an inheritable mutation)
how do germline mutations affect the risk of developing cancer
This does increase your risk of developing cancer BUT does not necessarily mean you will develop cancer immediately
how is germline mutation different to somatic mutation
germline mutation:
inheritable mutation
somatic mutation:
Cannot be passed on, found in daughter cells during cell division but it is NOT inheritable
describe the process of tumour formation from a single somatic cell
alteration in DNA of somatic cell
All cells in a primary tumour arise from a single cell: initiation of the
development of cancer is clonal
cell division of mutated cell = production of clonal cells = tumour formation
what do tumours that arise from somatic mutations do to help themselves survive
what is meant by sub clonal mutations?
It is the continued accumulation of mutations within the tumour (the tumour will continue to evolve and accumulate changes to help themselves survive)
clones that has arised from the same transformed cell but that have accumulated different mutations in them to help the tumour survive (this also explains the heterogeneity of cells in a tumour). this also explains why cells from the same tumour respond differently to treatment.
normal cells can receive signals to stimulate proliferation. What are 3 examples of these signals/
- growth factors (PDGF, EGF)
- cytokines (growth hormone, IL)
- hormones (oestrogen)
in terms of proliferation and apoptosis, what is the balance between these in healthy cells?
proliferation = cell loss
HEALTHY CELLS
how do tumours arise from a normal cell
there are many genes involved in the regulation of the growth, apoptosis and differentiation of cell numbers
mutation in the genes that regulate these processes can lead to an imbalance between proliferation and cell loss
uncontrolled cell proliferation = tumour formation
what are the 2 categories of genes that regulate cell growth
oncogenes
tumour suppressor genes
what is the difference between oncogenes and proto-oncogenes
a proto oncogene codes for proteins responsible for cell proliferation
proto oncogene –> activated oncogene via mutation = leads to signals that cause uncontrolled growth
(tumour formation = cancer)
Role of tumour suppressor genes
Tumour suppressor genes inhibit both growth and tumour formation
They act as breaking signals during G1 phase of the cell cycle, to stop or slow the cell cycle before S phase (before DNA replication)
what happens if there is a mutation in the tumour suppressor gene
If tumour-suppressor genes are mutated, the normal brake mechanism will be disabled, resulting in uncontrolled growth (progression of cell cycle = tumor formation = cancer)
the formation of a tumour occurs as a result of changes to which 2 genes and what changes occur
This means the formation of a tumour as a result of:
1. mutation in proto-oncogene —> activated oncogene
- mutation in tumour suppressor gene
What are the 3 assumptions made for carcinogenesis models?
- Malignant transformation of a single cell is sufficient to give rise to a tumour
- Any cells in a tissue are equally likely to be transformed
- Once a malignant cell is generated the mean time to tumour detection is generally constant
What are the 5 models of cancer?
Model 1: mutational (genotoxic)
Model 2: genome instability
Model 3: non-genotoxic
Model 4: Darwinian(evolving tumour)
Model 5: tissue organisation
what are the 4 carcinogens categories
chemical
physical
heritable (predisposition)
viral
examples of chemical carcinogens
polycyclic aromatic hydrocarbons
aromatic amines
nitrosamines
alkylating agents
examples of physical carcinogens
radiation such as ionising and UV
examples of viral carcinogens
hepatitis B
Epstein Barr
What are the 4 major groups that exert their carcinogenic effects by adding functional groups to DNA bases called DNA adducts?
- Polycyclic aromatic hydrocarbons
- Aromatic amines
- Nitrosamines
- Alkylating agents
What is found in coal tar and how is this related to cancer?
Coal tar contains benzo(a)pyrene.
It enters cells VERY easily and when activated can become carcinogenic
describe benzo(a)pyrene and how it is related to cancer
where is it commonly found - how does it get into our bodies?
Benzo(a)pyrene (BP) is a procarcinogen (NOT CARCINOGENIC)
When BP is taken into our bodies (via cigarette smoke) and is acted upon by microsomal enzymes, it is converted into Benzo(a)pyrene epoxide via addition of functional group.
This is when it becomes carcinogenic.
What effect does Benzo(a)pyrene epoxide have on DNA?
IT IS A CARCINOGEN
Changes G—-> T in DNA
What test can be carried out to find out if something is carcinogenic?
Ames Test
A test to determine the mutagenic activity of chemicals by observing whether they cause mutations in sample bacteria
mutation in bacteria = chemical is carcinogenic
how does the Ames test work
You take rat liver extract (contains the microsomal enzymes), you mush it up and you combine it with a Salmonella strain that will only grow in the presence of histidine.
If you plate that onto an agar plate that lacks histidine, following overnight incubation, you should have very few colonies on that plate.
(If you get one or two, it’s due to natural reversion)
If you add the carcinogen being tested, and then plate it, and then you get lots of colonies, it suggest that there is now a change in the bacteria, and it can now grow in the absence of histidine. This confirms that the compound you’re testing is in fact carcinogenic.
How do physical carcinogens act?
Unlike chemical carcinogens physical carcinogens act by imparting energy into the biological material
Physical carcinogens include radiation. What 2 types can act as carcinogens?
ionising radiation
(x-ray, nuclear radiation)
UV radiation
How does radiation act on DNA?
Is this reversible?
Radiation is a physical carcinogen
Radiation damages DNA by causing DNA breaks or pyrimidine dimers
These damages can be repaired BUT if not this leads to failed repair which leads to translocations and mutations
Describe heritable carcinogens and the relation to cancer
An inherited germline mutation has an increased risk of developing certain tumours but are RARELY involved in CAUSING cancer immediately
in hereditary malignant syndromes, what is the elevated cancer risk due to
In most hereditary malignant syndromes, the elevated cancer risk is due to a mutation of a single gene
(monogenic hereditary diseases)
How could heritable carcinogens lead to an increase risk of cancer
most cases = mutation of a single gene
The affected genes usually have a controlling function on the cell cycle, apoptosis or the repair of DNA damage
A deficiency in DNA repair would cause more DNA damages to accumulate, and increase the risk for cancer (predisposition for cancer)
What are germline mutations?
can it be inherited
Present in egg or sperm
Can be inherited
Cause cancer family syndrome
what are the 2 groups of syndrome predisposing to cancer
DNA repair defects
chromosomal abnormalities
examples of DNA repair defects predisposing to cancer
- Ataxia telangiectasia
- Bloom’s syndrome
- Fanconi’s anaemia
- Li-Fraumeni syndrome
- Lynch type II
- Xeroderma pigmentosum
examples of chromosomal abnormalities predisposing to cancer
- Down’s syndrome
* Klinefelter’s syndrome
What is Ataxia telangiectasia (‘spider veins’)?
mutation in what gene?
- Neuromotor dysfunction
- Dilation of blood vessels
- Mutation in ATM gene
what is the ATM gene
Codes for serine/threonine kinase (its function is to phosphorylate P53) that is recruited and activated by dsDNA breaks leading to cell cycle arrest, DNA repair and apoptosis
ATM gene codes for serine/threonine kinase.
What is the function of serine/threonine kinase
its function is to phosphorylate P53
what can mutation in the ATM
mutation in gene = improper function in DNA repair etc
What is Ataxia telangiectasia (‘spider veins’) a cancer predisposition for
Lymphoma
Leukaemia
Breast cancer
blooms syndrome
what do people with this look like? (in terms of height)
what happens in this syndrome?
short stature (rarely exceed 5ft)
skin rash that develops after skin exposure
what happens in Bloom syndrome
mutation of BLM gene
what is the function of the BLM gene
Provides instructions for coding a member of the RecQ helicase family that help maintain the structure and integrity of DNA
what is Bloom syndrome a cancer predisposition for
Basal cell carcinoma
Squamous cell carcinoma
What is Lynch type II?
Mutation in DNA mismatch repair genes (MMR genes):
MLH1
MSH2
MSH6
PMS2
what is Lynch type II a cancer predisposition for
colorectal cancer
sign of Lynch type II
NO SYMPTOMS
First sign that a person has Lynch type II is when symptoms of bowel and womb cancer develops
Describe viruses as carcinogens
Most harm is caused when viruses multiply inside the infected cell, kill the cell (lysis) and release progeny to further infect other cells
In rare incidences it switches to a latent cycle
BUT
Some viruses can be tumorigenic (allow transformation of cells; tumour formation)
What are some properties required of tumorigenic viruses? (3)
stable association with cells
must not kill cells
must evade immune surveillance of infected cells
how do tumorigenic viruses form a stable association with cells
- chromosomal integration
- episome(can replicate independently of chromosomal DNA)
how do tumorigenic viruses ensure they do not kill host cells
- non-permissive host (virus cannot replicate)
- suppression of viral lytic cycle
- viral release by budding
how do tumorigenic viruses evade immune surveillance
- immune suppression
- viral antigens not expressed at cell surface
List some viruses that are associated with human cancer and the type of cancer they can result in
- DNA VIRUSES
- RNA VIRUSES
DNA VIRUSES
1. Epstein-Barr virus
• Burkitt’s lymphoma
• Nasopharyngeal carcinoma
- Papilloma virus
• Cervical carcinoma
• Warts - Hepatitis B and C
• Hepatoma
RNA RETROVIRUSES
• HTLV-I (Adult T-cell leukaemia, lymphoma)
What is retinoblastoma?
A childhood cancer that affects the retina
What causes retinoblastoma?
RB1 (the tumour suppressor gene) causes retinoblastoma when BOTH COPIES are mutated
DESCRIBE Knudson’s hypothesis for hereditary cancers
Knudson found that there were 2 sets of patients:
- Patients presenting with the tumour at an early age
- Patients presenting with the tumour at a later age
He then found out this was because there are 2 types of retinoblastoma:
- The inherited form (as a result of a mutation in the Rb gene)
- The sporadic form
in the inherited form, the patients would have acquired the second mutations (and therefore both) at a much earlier age than the sporadic (non inherited) form.
In the sporadic forms of the tumour both mutations had to take place and hence this could explain the difference of age at diagnosis.
Stage at which they would have acquired BOTH mutations and therefore retinoblastoma?
inherited = earlier in life
sporadic = later in life
describe the non genotoxic model of cancer
Non-genotoxic carcinogens have been shown to act as:
- tumour promoters
- endocrine-modifiers
- receptor-mediators
- immunosuppressants
- inducers of tissue-specific toxicity and inflammatory responses
example of non genotoxic carcinogen that acts as tumour promoters
1,4-dichlorobenzene
example of non genotoxic carcinogen that acts as endocrine modifiers
17β-estradiol
example of non genotoxic carcinogen that acts as receptor mediators
2,3,7,8-tetrachlorodibenzo-p-dioxin
example of non genotoxic carcinogen that acts as immunosuppressants
cyclosporine
example of non genotoxic carcinogen that acts as inducers of tissue-specific toxicity and inflammatory responses
metals such as arsenic and beryllium
describe the darwinian model of carcinogens
- carcinogen exposure = normal cell accumulates mutations
- Natural selection
This mutated cell will undergo changes to form a tumour (transformation) - Tumour cells will be selected for ability to grow and invade
(This tumour cell will also undergo artificial selection: when treating a patient with chemotherapy some tumour cells become resistant to the treatment = these tumour cells will therefore be able to expand and grow)
There can be the ODD mutation that is a disadvantage to the tumour cell (rare)
Describe model 5: tissue organisation
Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research
What are they?
- Somatic mutation theory (SMT)
2. Tissue organisation field theory (TOFT)
Describe the somatic mutation theory (SMT)
Cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations.
Those mutations damage the genes which control cell proliferation and the cell cycle.
If these changes are not repaired = carcinogenesis
Describe the tissue organization field theory (TOFT)
Carcinogenic agents destroy the normal tissue architecture, thus disrupting cell-to-cell signalling and compromising genomic integrity.
The DNA mutations are random and the effect of the tissue disruption, not the cause
What is the immune system’s response to cancer?
does this get rid of the cancer?
The immune system will:
- protect from virus-induced tumours
- eliminate pathogens
- identify and eliminate tumour cells
This leads to immune surveillance. However, despite this, tumours can still arise.
What is cancer immunoediting?
ELIMINATION:
The immune system is able to eradicate developing tumours.
However some tumours are able to escape elimination and go onto equilibrium (cancer persistence)
EQUILIBRIUM (cancer persistence)
When incomplete removal is present, tumour cells remain dormant and enter equilibrium. The immune system exerts a potent and relentless pressure that contains the tumour. During this phase, some of the tumour may mutate or give rise to genetic variants that survive, grow and enter the next phase
ESCAPE (cancer progression)
The expanding tumour populations becomes clinically detectable.
describe the mutational (genotoxic) model of cancer
Carcinogens can directly alter the structure of DNA (genotoxic), if this change in DNA is not repaired then it leads to an increased chance in developing a tumour.
The presence of multiple mutations in critical genes in a distinctive feature of cancer cells and supports that cancer arises through the accumulation of irreversible DNA damage